4-Naphthyl and substituted naphthyl-3-hydroxy-3-pyrroline-2,5-diones and their use as inhibitors of glycolic acid oxidase

ABSTRACT

Novel 4-substituted-3-hydroxy-3-pyrroline-2,5-diones are disclosed which inhibit glycolic acid oxidase and thus are useful in the treatment and prevention of calcium oxalate kidney stone formation. A novel process for their preparation is also disclosed.

This is a division of application Ser. No. 091,293 filed Nov. 5, 1979,now U.S. Pat. No. 4,349,561, issued Sept. 14, 1982.

BACKGROUND OF THE INVENTION

Close to 70% of kidney stones in man are composed partially orpredominantly of calcium oxalate. There is no satisfactory drug specificfor the treatment of calcium oxalate renal lithiasis, nor forprophylactic use by patients prone to recurrent attacks of this disease.

The most common treatment for renal lithiasis due to calcium oxalateconsists of surgical removal of stones, control of the diet to restrictcalcium or oxalate, and ingestion of large quantities of water to dilutethe urine. Attempts at chemotherapy have included the administration ofmagnesium oxide, calcium carbimide, orthophosphate, cellulose phosphate,isocarboxazide, thiazide diuretics, allopurinol and succinimide. Limitedsuccess has been realized by these drug approaches. No drug whichspecifically inhibits the biosynthetic formation of oxalic acid haspreviously been developed for the treatment of calcium oxalate renallithiasis.

The immediate metabolic precursor of the majority of the oxalate in theurine of a typical patient is glyoxylic acid. In turn its most importantprecursor is glycolic acid. The enzyme glycolate oxidase is able tocarry out the oxidation of glycolic acid, through glyoxylic acid, tooxalic acid. Inhibition of this enzyme will, therefore, reduce theconcentration of oxalic acid in the kidney and bladder, decreasing theprobability that calcium oxalate crystallization will occur. Thusinhibitors of glycolate oxidase provide a specific approach to theprevention and treatment of calcium oxalate renal lithiasis.

Liao, et al, Arch, Biochem, Biophys., 154, 68-75 (1973) have shown thatphenyllactic acid and n-heptanoic acid, which are inhibitors ofglycolate oxidase, inhibit oxalate biosynthesis in isolated perfused ratliver. These compounds are not sufficiently potent to be useful asdrugs.

The preparation of 3-hydroxy-4-phenyl-3-pyrroline-2,5-dione ##STR1## hasbeen described by Harlay, J. Pharm. Chim., 24, 537-48 (1936).3-Hydroxy-4-aryl-3-pyrroline-2,5-diones are described in U.S. Pat. No.3,349,263 as intermediates in the preparation of antiphlogisticsubstances. A number of3-hydroxy-4-substitutedphenyl-3-pyrroline-2,5-diones are reported by G.S. Skinner, et al., J. Am. Chem. Soc., 73, 2230 (1951). (In this paperthese compounds are referred to as pyrrolidine-2,3,5-trionederivatives). 3-Hydroxy-4-(4-bromo-1-naphthyl)-3-pyrroline-2,5-dione isdescribed by G. S. Skinner, et al., J. Am. Chem. Soc., 70, 4011(1948).

Compounds of the structure ##STR2## are disclosed in a previous patentapplication by J. Rokach, E. J. Cragoe, Jr. and C. S. Rooney now U.S.Ser. No. 930,103 where these preparations are also described. Compoundsof this type are covered in this invention only by the method of useclaim (i.e. just claims to use for renal lithiasis).

SUMMARY OF THE INVENTION

It has now been found that compounds of the formula: ##STR3## wherein nis 0 or 1;

Y is CH₂ --CH₂ ; CH═CH; CH₂ --O; O--CH₂ ;

R₁ and R₂ are both hydrogen, hydrogen and hydroxyl or taken together are═O;

R₃ is hydrogen or halogen; particularly compounds having the structure##STR4## wherein n is 0 or 1;

the dotted line indicates saturation or unsaturation;

R₁ and R₂ are both hydrogen, hydrogen and hydroxyl or taken together are═O;

R₃ is hydrogen or halogen and compounds having the structural formula:##STR5## wherein R₄ is hydrogen, halogen, loweralkoxy containing 1 to 6carbon atoms or ##STR6## or a pharmaceutically acceptable salt thereofare potent inhibitors of glycolate oxidase. They are, therefore, usefulin the treatment and prevention of calcium oxalate kidney and bladderstone formation.

Included in the present invention are novel compounds having thestructural formula: ##STR7## wherein Y is CH₂ --CH₂ ; CH═CH; CH₂ --O;O--CH₂ ;

R₁ and R₂ are both hydrogen, hydrogen and hydroxyl or taken together are═O;

R₃ is hydrogen, or halogen; and particularly those novel compoundswherein

Y is CH₂ --CH₂ ; CH═CH;

R₁ and R₂ are both hydrogen, hydrogen and hydroxyl or taken together are═O;

R₃ is hydrogen or halogen; having the structural formula: ##STR8##wherein the dotted line indicates saturation or unsaturation.

Also included are novel compounds having the structural formula:##STR9## wherein R₁ and R₂ are both hydrogen, hydrogen and hydroxyl, ortaken together are ═O;

R₃ is hydrogen or halogen.

Other types of novel compounds included in this invention are those withthe structural formulae ##STR10## wherein R₁ and R₂ are both hydrogen,hydrogen and hydroxyl, or taken together are ═O;

R₃ is hydrogen or halogen.

Also included in the present invention are novel compounds having thestructural formula: ##STR11## wherein R₄ is hydrogen, halogen,loweralkyl containing 1 to 6 carbon atoms or ##STR12## andpharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION

About 70% of all renal calculi contain oxalate as the main component ofthe matrix. In the majority of patients the condition is associated witha higher than average level of metabolically produced oxalate. The majorpathway for biosynthesis of oxalate can be represented as follows:##STR13## Glyoxylate is the major immediate forerunner of oxalate. Aninhibitor of glycolate oxidase (G.O.) will inhibit both the conversionof glyoxylate to oxalate as well as the production of glyoxylate fromglycolate. By reducing oxalic acid levels in the urine with thecompounds of this invention, the formation of oxalate calculi will bereduced or prevented.

Compounds of formula (I) are potent inhibitors of glycolate oxidase andthus are useful in restricting oxalate levels in the blood and urine.Further, they are useful in the treatment and prevention of renaldisease due to calcium oxalate stone formation in the kidney andbladder. They may also be useful in the treatment of the geneticallyinherited diseases termed Hyperoxaluria types I and II.

Compounds of formula (I) have been unexpectedly found to block thecontractions of guinea pig ileum induced by Slow Reacting Substance ofAnaphylaxis (SRS-A). They are ineffective against contractions caused byhistamine, which demonstrates specificity against SRS-A. SRS-A isconsidered a major mediator in human allergic asthma. Thus the compoundsof formula (I) are useful in the treatment of allergy, especiallyallergic asthma.

Compounds of formula (I) can be prepared according to the followingroutes:

General Routes for 4-Substituted-3-hydroxy-3-pyrroline-2,5-dioneSynthesis ##STR14## The following general routes to the syntheses of theabove ester (or nitrile) intermediates are applicable to compounds ofthis invention. ##STR15## The reactions with ethyl bromoacetate orchloroacetonitrile are applicable to the synthesis of those derivativeswhere in (O)_(n), n=1. Route 4 is applicable primarily to thenaphthalene derivatives of this invention, the synthesis of which canstart with the known 6-hydroxy-2-acetonaphthone. Synthesis of thedibenzo[a,d]cycloheptene and dibenzo[b,e]oxepin acetic acid esterintermediates of this invention are by routes specific for those groupsof compounds.

In Routes, 1, 2, 3 and 4, R represents substituents at the 4-position ofthe 3-hydroxy-3-pyrroline-2,5-dione in formula (I) above.

The following examples, given by way of illustration and not to beconstrued as limiting, further clarify the invention.

Procedure for the Preparation of Substituted Naphthylacetophenones

The methyl ketone,6-(3-hydroxy-3,4-dihydro-2H-1,5-benzodioxepin-3-ylmethoxy)-2-acetonaphthone,was prepared by the following route, starting with6-hydroxy-2-acetonaphthone; ##STR16## 6-Loweralkoxy-2-acetonaphthonesare prepared by reaction of 2-alkoxynaphthalenes with acetylchloride andaluminum trichloride under Friedel-Craft conditions.

EXAMPLE 1 Preparation of6-(3-Hydroxy-3,4-dihydro-2H-1,5-benzodioxepin-3-ylmethoxy)-2-acetonaphthone

A mixture of 6-hydroxy-2-acetonaphthone (186 mg, 1 mmole),3,4-dihydro-2H-1,5-benzodioxepin-3-spirooxirane (178 mg, 1 mmole) andn-butanol (2 ml) containing 1 drop of detergent base (40% Triton B) inmethanol was heated at 120° C. for 24 hours. An additional drop ofdetergent base solution was added and after another 24 hours, anotherdrop of detergent base was added. After another 24 hours at 120° C., themixture was evaporated to dryness, and the residue was purified bypassing a solution in chloroform down a short column of silica gel (6g). The eluate was evaporated to dryness and the residue crystallizedfrom acetonitrile (˜1 ml) to give 192 mg (53%) of product, mp131°-132.5° C.

Analyzed for C₂₂ H₂₀ O₅ : Required: C, 72.51; H, 5.53; Found: C, 72.54;H, 5.70.

General Procedure for the Preparation of Methyl Substituted Arylacetates(IV) Route 4. Step 1

Substituted acrylacetic acid esters (IV), were made by the oxidativerearrangement of the corresponding methyl ketones (III) by the method ofE. C. Taylor and A. McKillop, J. Amer. Chem. Soc., 93, 4919 (1971), ibid95, 3340 (1973). Two examples of substituted acrylacetic acid ester (IV)prepared by this process are set forth in Table I below.

                                      TABLE I                                     __________________________________________________________________________                                   Yield                                                                             MP °C.                                                                            Analysis                        Compound IV                    %   Solvent                                                                             Formula                                                                              Req.                                                                             Fd.                        __________________________________________________________________________     ##STR17##                     61  106-108 diisopropyl ether                                                           C.sub.23 H.sub.22 O.sub.6                                                          C H                                                                             70.04  5.62                                                                      70.30  5.87                methyl 6-(3,4-dihydro-3-                                                      hydroxy-2H1,5-benzodioxepin-                                                  3-ylmethoxy)-2-naphthylacetate                                                 ##STR18##                     88 (crude)                                                                        75-77 petroleum ether                                                               C.sub.14 H.sub.14 O.sub.3                                                          C H                                                                             73.02  6.12                                                                      73.40  6.53                methyl 6-methoxy-2                                                            naphthylacetate                                                               __________________________________________________________________________

General Procedure for Preparing Aryloxyacetic Acid Esters

The general procedure for the preparation of aryloxyacetic acid esterderivatives is as follows:

The phenol intermediate (10 m mole) is added to a solution of sodium (10m mole) in ethanol (20 ml) (i.e., sodium ethoxide) under nitrogen. Tothe cooled mixture is added ethyl (or methyl) bromoacetate (10 mmole) inethanol (10 ml), and then the mixture is stirred for up to twelve hoursat room temperature in order to complete the reaction. The ester isisolated by addition of water, extraction into chloroform andevaporation of the chloroform. The crude ester, in general, issufficiently pure to be used directly in the amide forming step.

When 2-hydroxy-10,11-dihydro-5H-dibenzo-[a,d]cycloheptene is utilized asstarting material in this reaction, there is obtained ethyl10,11-dihydro-5H-dibenzo[a,d]cyclohepten-2-yloxyacetate.

When 3-hydroxy-10,11-dihydro-5H-dibenzo[a,d]cycloheptene is used asstarting material in this reaction there is obtained ethyl10,11-dihydro-5H-dibenzo[a,d]cyclohepten-3-yloxyacetate.

When 2-hydroxy-5H-5-oxodibenzo[a,d]cycloheptene is used as startingmaterial in this reaction there is obtainedethyl-5H-5-oxodibenzo[a,d]cycloheptene-2yloxyacetate.

When 3-hydroxy-10,11-dihydro-5H-5-oxodibenzo[a,d]cycloheptene isutilized as starting material in this reaction there is obtained ethyl10,11-dihydro-5H-5-oxodibenzo[a,d]cyclohepten-3-yloxyacetate.

When 2-hydroxy-6,11-dihydro-11-oxodibenz[b,e]oxepin is used as startingmaterial for this reaction there is obtained ethyl6,11-dihydro-11-oxodibenz[b,e]oxepin-2ylacetate.

When 4-hydroxy-6,11-dihydro-11-oxodibenz[b,e]oxepin is used as startingmaterial for this reaction there is obtained ethyl6,11-dihydro-11-oxodibenz[b,e]oxepin-4-ylacetate.

General Procedure for Preparing the Substituted Acetamides (V) Route 2,Step 3

The substituted acetic acid esters (IV) are converted to thecorresponding amides (V) by treatment with 71/2 parts by weight of asaturated solution of ammonia in methanol at room temperature.Conversion to the amide is followed by thin layer chromatography and mayrequire several days. Examples of substituted acetamides (V) prepared bythis process are set forth in Table II below.

                                      TABLE II                                    __________________________________________________________________________                                Yield                                                                             MP °C.                                                                            Analysis                           Compound                    %   Solvent                                                                            Formula Req.                                                                             Fd.                           __________________________________________________________________________     ##STR19##                  62  201-202 MeOH                                                                       C.sub.22 H.sub.21 NO.sub.5                                                          C H N                                                                           69.64  5.57  3.69                                                                69.34  5.60  3.               6-(3,4-dihydro-3-hydroxy-                                                     2H1,5-benzodioxepin-3-                                                        ylmethoxy)-2-naphthyl-                                                        acetamide                                                                      ##STR20##                  55  242-245 DMF                                                                        C.sub.13 H.sub.13 NO.sub.2                                                          C H N                                                                           72.54  6.08  6.50                                                                72.71  6.30  6.               6-methoxy-2-naphthyl-                                                         acetamide                                                                      ##STR21##                  77 overall                                                                        133-135 EtOAc                                                                      C.sub.17 H.sub.15 NO.sub.3                                                          C H N                                                                           72.58  5.3  4.97                                                                 72.14  5.61  4.88             10,11-dihydro-5-oxo-5H                                                        dibenzo[a,d]cyclohepten-                                                      3-yloxyacetamide                                                               ##STR22##                  59 overall                                                                        147-150 MeOH                                                                       C.sub.17 H.sub.17 NO.sub.2                                                          C H N                                                                           76.38  6.40  5.23                                                                76.19  6.60  5.14             10,11-dihydro-5Hdibenzo-                                                      [a,d]cyclohepten-3-                                                           yloxyacetamide                                                                __________________________________________________________________________

When methyl (10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetateis utilized as the starting material in this reaction there is obtained(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetamide.

When ethyl [(6,11-dihydro-11-oxodibenzo-[b,e]-oxepin-2-yl)oxy]acetate isused as the starting material in this reaction, there is obtained[(6,11-dihydro-11-oxodibenzo[b,e]oxepin-2-yl)oxy]acetamide.

When ethyl 5H-5-oxodibenzo[a,d]cyclohepten-2-yl-oxyacetate is used asstarting material in this reaction there is obtained5H-5-oxodibenzo[a,d]cyclohepten-2-acetamide.

When ethyl 6,11-dihydro-11-oxodibenz[b,e]oxepin-4-ylacetate is used asstarting material in this reaction there is obtained6,11-dihydro-11-oxodibenz[b,e]oxepin-4-yl-acetamide.

EXAMPLE 2 General Method for the Preparation of3-Hydroxy-4-substituted-3-pyrroline-2,5-diones from AcetamideIntermediates Routes 1 and 2, Step 4

A mixture of the substituted acetamide (10 mmole), diethyl oxalate(1.533 g, 10.5 mmole) and dry dimethylformamide (20 ml) is stirred undernitrogen or argon and cooled in an ice-bath. Potassium t-butoxide (2.464g, 22 mmole) is added in two equal portions 15 minutes apart and thereaction mixture is stirred for about 30 minutes in the ice-bath andthen at room temperature overnight. The reaction mixture is poured intoice-water (100 ml). If the potassium salt of the product dissolves, theaqueous mixture is extracted with ethyl acetate (2×35 ml) and thenacidified with 6 N hydrochloric acid in order to precipitate theproduct. The product is either collected by filtration or by extractionwith ethyl acetate.

If the potassium salt is not soluble when the reaction mixture isquenched in ice-water, then it is necessary to acidify the resultingsuspension and collect the product by filtration. The crude product isgenerally less pure when obtained in this way.

The compounds may be solvated after recrystallization (with either DMF,dioxane, isopropanol or acetonitrile) and require drying at 110° C./0.05Torr in order to remove the solvate.

Examples of 3-hydroxy-4-substituted-3-pyrroline-2,5-diones prepared bythis process are set forth in Table III below:

                                      TABLE III                                   __________________________________________________________________________                                   Yield                                                                              MP °C.  Analysis                   Compound (I)                   %    Solvent Formula  Req.                                                                             Fd.                   __________________________________________________________________________     ##STR23##                     42   285-287 THF/MeCN                                                                      C.sub.24 H.sub.19 NO.sub.7                                                           C H N                                                                           66.51  4.42                                                                      66.45  4.35  3.55     3-hydroxy-4-[6-(3,4-dihydro-3-                                                hydroxy-2H1,5-dibenzoxepin-3-                                                 ylmethoxy)-2-naphthyl]-3-                                                     pyrroline-2,5-dione                                                            ##STR24##                     35   278-280 dec. EtOAc                                                                    C.sub.18 H.sub.11 NO.sub.5                                                           C H N                                                                           67.29  3.45                                                                      67.11  3.40  3.90     3-hydroxy-4-(11-oxo-6,11-                                                     dihydrodibenzo[b,e]oxepin-                                                    2-yl)-3-pyrroline-2,5-dione                                                    ##STR25##                     58   265-267 i-PrOH                                                                        C.sub.15 H.sub.11 NO.sub.4                                                           C H N                                                                           66.91  4.11                                                                      67.0  4.31  5.36      3-hydroxy-4-(6-methoxy-2-                                                     naphthyl)-3-pyrroline-2,5-                                                    dione                                                                          ##STR26##                     58   115-117 EtOAc                                                                         C.sub.19 H.sub.13 NO.sub.5.                                                   C.sub.3 H.sub.7 NO                                                                   C H N                                                                           64.70  4.94                                                                      64.93  5.07  6.76     3-hydroxy-4-(3-oxo-10,11-                                                     dihydrodibenzo[a,d]cyclohepten-                                               3-yloxy)-3-pyrroline-2,5-                                                     dione dimethylformamide solvate                                                ##STR27##                          toluene C.sub.19 H.sub.15 NO.sub.4.                                                   11/4 H.sub.2 O                                                                       C H N                                                                           66.37  5.12                                                                      66.71  5.07,                                                                  3.91,                                                                             66.15  5.39                                                                   4.13              3-hydroxy-4-(10,11-dihydro-                                                   dibenzo[a,d]cyclohepten-3-                                                    yloxy)-3-pyrroline-2,5-dione                                                  __________________________________________________________________________

When (10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetamide isemployed as the starting amide there is obtained4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-on-2-yl)3-hydroxy-3-pyrroline-2,5-dione.

When [(6,11-dihydro-11-oxodibenzo[b,e]-oxepin-2-yl)oxy]acetamide isemployed as the starting amide there is obtained4-[(6,11-dihydro-11-oxodibenzo[b,e]oxepin-2-yl)oxy]-3-hydroxy-3-pyrroline-2,5-dione.

When 2-(5H-5-oxodibenzo[a,d]cyclohepten-5-on-3-yl)acetamide is employedas the starting material, there is obtained4-(5H-5-oxodibenzo[a,d]cyclohepten-5-on-3-yl)-3-hydroxy-3-pyrroline-2,5-dione.

When 6,11-dihydro-11-oxodibenz[b,e]oxepin-4-yl-acetamide is employed asstarting material, there is obtained4-(6,11-dihydro-11-oxodibenz[b,e]oxepin-4-yl)-3-hydroxy-3-pyrroline-2,5-dione.

General Method for the Preparation of3-Hydroxy-4-Substituted-3-pyrroline-2,5-diones from SubstitutedAcetonitrile Intermediates

A mixture of the substituted-acetonitrile (10 mmole), diethyl oxalate(1.53 g, 10.5 mmole) and dry dimethylformamide (20 ml) is stirred undernitrogen or argon and cooled in an ice-bath. Potassium t-butoxide (2.46g, 22 mmole) is added in two equal portions 15 minutes apart and thereaction mixture is stirred for about 30 minutes in the ice-bath, andthen overnight. Most of the dimethylformamide is evaporated in vacuo. Tothe residue is added water (50 ml) and ethyl acetate (100 ml). Themixture is made acidic (pH4-5) with dilute hydrochloric acid. The ethylacetate phase after washing with water, and drying (MgSO₄) isevaporated. The residue is dissolved in cooled sulfuric acid (8 ml) andthe solution allowed to stand at room temperature for 18 hours. The acidsolution is poured onto ice, or mixed with 90% ethanol-H₂ O (100 ml) toobtain the hydroxypyrrolinedione. The crude hydroxypyrrolinedione isrecovered by filtration after the ice has melted (or evaporation of theethanol from the ethanol-water mixture if the latter is used).

When 5H-diobenzo[a,d]cyclohepten-5-on-2-yl-acetonitrile (J. Med. Chem.20, 1557 (1977)) is treated by the above procedure there is obtained4-(5H-dibenzo[a,d]-cyclohepten-5-on-2-yl)-3-hydroxy-3-pyrroline-2,5-dione.

When 7-chloro-5H-diobenzo[a,d]cyclohepten-5-on-2-ylacetonitrile istreated according to the above procedure there is obtained4-(7-chloro-5H-dibenzo[a,d]cyclohepten-5-on-2-yl)-3-hydroxy-3-pyrroline-2,5-dione.The 7-chloro-5H-dibenzo[a,d]cyclohepten-2-ylacetonitrile is preparedaccording to the procedure described in the above reference using methyl5-chloro-2-methylbenzoate as starting material.

Preparation of Tricyclic Hydroxypyrrolinedione Derivatives where R₁, R₂=H,OH

For preparation of tricyclichydroxypyrrolinedione derivatives in whichthe central carbon is substituted with a hydroxyl group thecorresponding keto tricyclicacetamide intermediate is reduced usingsodium borohydride in ethanol at 0°-50° C. The reduced amideintermediates are then reacted with diethyl oxalate and potassiumt-butoxide in dimethylformamide to give the final hydroxypyrrolinedionederivatives (R₁, R₂ =H,OH) according to the procedure of Example 2.

EXAMPLE 3 Preparation of2-[(10,11-Dihydro-5-hydroxy-5H-dibenzo[a,d]cyclohepten-3-yl)oxy]acetamide

Sodium borohydride (0.076 g, 2 mmole) is added in portions to a mixtureof [(10,11-dihydro-5-oxo-5H-dibenzo[a,d]cyclohepten-3-yl)oxy]acetamide(0.28 g, 1.0 mmole) in ethanol (40 ml) with stirring at roomtemperature. The mixture is stirred for 3 hours, and then the ethanolevaporated. The residue is slurried with water and filtered to give theabove intermediate.

This intermediate when reacted with diethyl oxolate, potassiumt-butoxide in dimethylformamide (as described in the general procedureof Example 2 for preparation of4-substituted-3-hydroxy-3-pyrroline-2,5-diones from acetamideintermediates) gives4-(10,11-dihydro-5-hydroxy-5H-dibenzo[a,d]cyclohepten-3-yl)-3-hydroxy-3-pyrroline-2,5-dione.

Included within the scope of the invention are the pharmaceuticallyacceptable salts of formula (I) compounds. The compounds of formula (I)are strong organic acids with a pKa in the range 2-4.These salts arereadily formed with the usual inorganic cations such as sodium,potassium and ammonium. Salts with organic amines such astrimethylamine, triethylamine, n-butylamine and the like are also verystable. The neutralization can be carried out by a variety of proceduresknown to the art to be generally useful for the preparation of suchsalts. The choice of the most suitable procedure will depend on avariety of factors including convenience of operation, economicconsiderations, and particularly the solubility characterisitics of theparticular free base, the acid, and the acid addition salt.

The compounds of formula (I) are utilized for the stated utilities byformulating them in a composition such as tablet, capsule or elixir fororal administration. Sterile solutions or suspensions can be used forparenteral administration. About 10 to 200 mg of a compound of formula(I) or a physiologically acceptable vehicle, carrier, excipient, binder,preservative, stabilizer, flavor, etc., in a unit dosage form as calledfor by accepted pharmaceutical practice. The amount of active substancein the composition is such that dosage in the range indicated isobtained. The total daily dose will be in the 30 to 2000 mg range,preferably 50 to 1000 mg.

Illustrative of the adjuvants which may be incorporated in tablets,capsules and the like are the following: a binder such as gumtragacanth, acacia, corn starch or gelatin; an excipient such asdicalcium phosphate; a disintegrating agent such as corn starch, potatostarch, alginic acid and the like, a lubricant such as magnesiumstearate; a sweetening agent such as sucrose or lactose; a flavoringagent such as peppermint, oil of wintergreen or cherry. When the dosageunit form is a capsule, it may contain in addition to materials of theabove type a liquid carrier such as a fatty oil. Various other materialsmay be present as coating or to otherwise enhance the pharmaceuticalelegance of the preparation. For instance tablets may be coated withshellac, sugar or the like. A syrup or elixir may contain the activecompound sucrose as a sweetening agent, methyl and propyl parabens aspreservatives, a dye and a flavoring such as cherry or orange flavor.

Sterile compositions for injection can be formulated according toconventional pharmaceutical practice by dissolving or suspending theactive substance in a conventional vehicle such as water for injection,a naturally occurring vegetable oil like sesame oil, coconut oil, peanutoil, cottonseed oil, etc., or a synthetic fatty vehicle like ethyloleate or the like. Buffers, preservatives, antioxidants and the likecan be incorporated as required.

What is claimed is:
 1. The compounds having the structural formula:##STR28## wherein R₄ is hydrogen, halogen, loweralkyl having 1 to 6carbon atoms or ##STR29## or a pharmaceutically acceptable salt thereof.2. A pharmaceutical composition composition for the treatment orprevention of calcium oxalate kidney or bladder stones comprising aneffective amount of a compound of claim 1 or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier.
 3. Amethod of treating or preventing the formation of calcium oxalate kidneyor bladder stones which comprises administering to a patient with orprone to renal lithiasis an effective amount of a compound having thestructural formula: ##STR30## wherein R₄ is hydrogen, halogen,loweralkyl having 1 to 6 carbon atoms or ##STR31## or a pharmaceuticallyacceptable salt thereof.